tbuckley/cabot-search huggingface dataset:
P01.11.A MECHANISMS OF LANGUAGE PLASTICITY IN PATIENTS HARBORING LEFT HEMISPHERE GLIOMAS
Authors: M Tate, M Ramsey, M Saxena
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Infiltrating gliomas are slow growing intrinsic brain lesions that have been shown to induce functional reorganization, although the mechanisms by which this occurs are not well understood. The present study examines glioma-induced neuroplasticity of language networks to investigate this phenomenon. MATERIAL AND METHODS 117 patients’ fMRI scans were analyzed from patients harboring gliomas whom completed 1-5 fMRI language tasks. Data was analyzed via two methods: cluster-based and cortical/subcortical mask-based. Right hemisphere gliomas (RHG) (n=40) were first analyzed to establish a reliable control group by determining statistically significant voxels across all five language tasks (LT), yielding a core conserved network. The language network induced by left hemisphere gliomas (LHG) (n=77) was then directly compared to the RHG language network to examine language plasticity. RESULTS LHG induced global reorganization of the canonical language network, including preserved homologous and novel left hemisphere (LH) and right hemisphere (RH) activation clusters. In each of the five LT, the LHG group showed activation of fewer total suprathreshold voxels in both the cluster (3 fewer clusters and 38,892 fewer active voxels/task) and mask-based (8 fewer active masks/task and 91,965 fewer active voxels/task) analyses while having a higher peak intensity (5.4 total increase in zmax) within the activated clusters. In addition, a generalized pattern of increased RH recruitment was seen in LHG patients, with 87% (137/157) of non-zero masks shifting their laterality index (LI) to the right hemisphere. These data suggest that the reorganized LHG-induced language network functions through less nodes along with a rightward shift of language lateralization. In addition, a subgroup analysis of frontal (n=16) and temporal (n=32) LHG revealed that frontal tumors promote increased RH activation relative to temporal tumors, with 94% (32/34) of non-zero masks shifting their LI to the RH compared to 68% (23/34), respectively. Frontal tumors also preferentially recruit the contralateral (RH) frontal lobe and ipsilateral (LH) temporal lobe, while temporal gliomas preferentially recruit the ipsilateral frontal lobe. CONCLUSION Infiltrating tumors within the left hemisphere promote language plasticity via consolidation of the classical LH language network along with recruitment of previously silent, novel language areas in the right and left hemispheres. This improved understanding of patterns of language plasticity may aid in more accurate pre-surgical risk stratification and counseling, therapeutic targeting for post-surgical recovery, and intelligent “pre-habilitation” strategies to maximize neuroplasticity prior to tumor resection.
P11.52.A LONG-TERM SURVIVORS OF GLIOBLASTOMA: A SINGLE-CENTRE RETROSPECTIVE STUDY
Authors: A Fortuna, P Luz, M Cordeiro
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, yet, despite advancements in understanding its biology, it remains an incurable disease with a high mortality rate. Less than 5% of patients survive beyond 5 years, making identification of factors associated with long-term survival critical in improving outcomes for patients with glioblastoma. MATERIAL AND METHODS In this retrospective study, we conducted a descriptive analysis of patients who were diagnosed with glioblastoma and survived for 19 months or longer after their initial diagnosis. We included patients discussed on the multidisciplinary tumour board from September 2020 to June 2022. RESULTS We evaluated 43 patients, 9 of these had a survival rate of more than 19 months, with a median survival of 25.53 months. The date of diagnosis ranged from May 2017 to August 2021. The majority were male (n=7). The median age at diagnosis was 58 years (minimum 35, maximum 73). Most had good performance status (PS): 4 had ECOG 0 and 4 had ECOG 1. Concerning tumor characteristics, most presented in the parietal lobe (n=7) and 6 were IDH wild type. Other genetic alterations were not evaluated. Four patients underwent macroscopic total resection, 3 underwent partial resection, 1 partial resection and subsequent total excision and 1 biopsy. All patients completed the STUPP protocol, with half of the patients on corticoids during the protocol. Of the 9 patients, 7 relapsed. After relapse, 2 patients underwent bevacizumab, 2 patients underwent total resection one with adjuvant STUPP protocol and one with adjuvant lomustine, 1 patient had radiotherapy and bevacizumab, 1 patient had bevacizumab and lomustine and 1 patient had temozolamide in monotherapy. Out of these, 6 patients had disease progression and only 4 received a second line of treatment. All 4 patients progressed and received treatment. Of these, 3 progressed and only 1 patient received therapy. At the end of follow-up, early April 2023, 4 patients were still alive. CONCLUSION With all these data profiles of long-term survivors of GBM and the pooled evidence from the literature, this extremely favorable prognostic group is still difficult to define. However, clinical and tumour characteristics of long-term survivors may differ from those of shorter-term survivors. In our series, long-term survivors were found to be IDH wild-type in the majority, young male, with good PS at the time of diagnosis and had GBM located in the parietal lobe. Larger series of patients and longer follow-up periods are needed to draw more robust conclusions about prognostic and predictive factors.
JS08.6.A CSF DERIVED LIQUID BIOPSIES FOR GLIOMA DIAGNOSIS
Authors: F Iser, C Güngör, J Meyer, L Dörner, L Hofmann, N Graßl, A Patel, B Wildemann, M Platten, W Wick, F Sahm, T Kessler
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Distinctive genetic changes can identify various types of gliomas. However, acquiring tumor material via surgery in the central nervous system (CNS) can pose the danger of neurological impairments, especially if the tumor is located near critical areas or in the brain stem. Gliomas discharge tumor DNA into the cerebrospinal fluid (CSF), where it mixes with circulating DNA from normal cells to generate cell-free DNA (cfDNA). Analyzing cfDNA via next-generation sequencing (NGS) is a substitute method for genomic assessments. MATERIAL AND METHODS We conducted targeted next-generation sequencing (NGS) of cerebrospinal fluid (CSF) cell-free DNA (cfDNA) using a panel that encompasses 130 genes from 81 patients with MRI detected suspicion of a primary (n = 69) or recurrent (n = 12) glioma. The library preparation and raw read data preprocessing were tailored specifically for cfDNA samples. To identify single nucleotide variants (SNVs) and small insertions and deletions (Indels), a classifier based on machine learning (somaticseq) was trained using cfDNA reference standards. The on- and off-target reads were employed to develop profiles of copy-number variations (CNVs) (cnvkit). RESULTS The sensitivity and specificity of short variant (SNV + Indel) calling were determined to range between 36.1% - 93.3% and 66.5% - 87.1%, respectively, depending on the input amounts (2ng to 4ng) of cfDNA reference material and the circulating tumor DNA (ctDNA) content (1% to 5%). In a group of 20 CSF samples from glioblastoma patients, the detected mutations and CNVs corresponded to those found in solid tissue samples. Furthermore, two additional patients with glial tumors in the brain stem that could not be accessed surgically were found to have an IDH:p.R132C mutation and a histone H3.3:p.K28M mutation, respectively. CONCLUSION A clinical workflow was developed with specific sensitivity and specificity values for sequencing cerebrospinal fluid (CSF) cell-free DNA (cfDNA). This workflow was tested on a group of glioblastoma patients with matched solid tumor tissue. In two patients with suspected glial tumors but no accessible tissue, the diagnosis was confirmed by identifying characteristic mutations.
P21.01.A EPIDEMIOLOGY OF ISCHEMIC LESIONS AFTER RESECTION OF LOW-GRADE GLIOMAS
Authors: T Dunås, A Lipatnikova, E Thurin, A Jakola
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Diffuse low-grade gliomas are slow-growing malignant brain tumors that mainly affect people in their 30s and 40s, usually resulting in death within a decade. The standard treatment is surgery, which has a moderate risk of neurological sequelae. Clinical experience indicates that not all sequels are directly related to the resected area but rather caused by collateral damage, such as tissue- and vascular damages at the surgical site, causing ischemic lesions in the surrounding tissue. In this study, the epidemiology of these lesions is investigated, in terms of how common they are and how they are related to the size, type and location of the tumor. MATERIAL AND METHODS One hundred and sixty-six patients who underwent resection for grade II glioma (WHO 2007 or 2016) between 2012 and 2017 at any of nine hospitals in Sweden and Norway and had a postoperative MRI scan including diffusion-weighted imaging within three days after surgery, were included in this study. Lesions were segmented on the b1000 image, using the ADC and T1 image to exclude hyperintense areas caused by other factors than ischemia. Statistical analyses were performed using IBM SPSS Statistics version 27.0 (IBM Corp., Armonk, NY, USA). Analyses were carried out with ischemic lesion size as a continuous variable, and since the volumes were not normally distributed, non-parametric tests were used. RESULTS Ischemic lesions were found in 146 out of 166 (88%) cases, the median volume of the segmented lesions was 1.9 ml, with an interquartile range (IQR) of 0.95-4.5 ml. Patients with new or worsened deficits did have significantly larger ischemic volumes than does who did not (1.7 vs 2.8 ml, p=0.03). Ischemic volume was significantly correlated to both pre- and post-operative tumor volume (Spearmans rho = 0.370 and 0.304, p&amp;lt;0.001). No difference in ischemic volume was found between astrocytoma and oligodendroglioma, based on reported histopathologic diagnosis (p=0.43) or molecular status (p=0.44), neither between main tumor local (frontal (60%) vs temporal (19%), parietal (8%) or insular (12%), p&amp;gt;0.37). CONCLUSION Ischemic lesions after glioma resection are very common, but mostly small and restricted to a region close to the resection cavity. Large ischemic regions were associated with new or worsened neurological deficits and were mostly found in association with large tumors. More fine-tuned measures might be needed to find potential associations between tumor local and ischemic lesions.
P11.19.A MACROPHAGES-BASED IMMUNOTHERAPY OF SOLID TUMORS MICROENVIRONMENT: THE TEM-GBM STUDY (NCT03866109)
Authors: M Eoli, B Gentner, E Anghileri, F Farina, A Capotondo, G D'Alessandris, F Di Meco, V Ferla, A Franzin, P Ferroli, F Gagliardi, F Legnani, S Mazzoleni, P Mortini, A Olivi, R Pallini, M Saini, S Snider, L Naldini, C Russo, F Ciceri, G Finocchiaro
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND We have developed an HSC-based platform to switch from pro-tumor to anti-tumor bone-marrow derived tumor-infiltrating macrophages. Specifically, Temferon cell therapy delivers IFN-a into the tumor microenvironment (TME) in a targeted manner via Tie-2 expressing monocytes, with transcriptional and post-transcriptional controls mediated by miRNA target sequences. MATERIAL AND METHODS TEM-GBM is an open-label, Phase 1/2a dose-escalation study evaluating the safety and efficacy of Temferon in up to 27 newly diagnosed, unmethylated MGMT glioblastoma (GBM) patients. Twenty-four patients are assigned to 8 cohorts and will receive a single increasing dose of Temferon, 3 additional patients will be further enrolled to confirm the safety profile of the chosen Temferon dose to be tested in a broader group of patients (Phase 2). Patients are followed up to 2 years after treatment with Temferon. Here we report the analysis on the biological activity of Temferon on patients who underwent a second surgery intervention. RESULTS As of 31st March 2023, 6 out of 19 Temferon treated patients underwent a second surgical intervention; of these, 4 belonged to low dose cohorts (C1-C2) and 2 to high dose cohorts (C4-C5). The second surgery occurred at a median of 11 months after 1st surgery (range 7-17 months). Where enough fresh material was collected to enrich for CD45+ cells within the tumor, a 3% to 5% of gene-marked tumor infiltrate was found (2/2 specimens) suggesting that Temferon-derived cells homed to the TME. To verify if the local delivery of IFN-a by TEMs was able to upregulate the Interferon Stimulated Genes (ISGs) in tumor tissue, the transcripts for IFIT1, IRF7, OAS1a genes were evaluated by RT-PCR in formalin-fixed paraffin sections obtained at first and second surgery. The analysis was performed on eighteen (18) 1st surgery samples (from C1 to C6), and on six (6) 2nd surgery specimens. At 1st surgery, transcripts were detected in 17 out of 17 specimens (one sample excluded since housekeeping genes did not amplify) and most of the patients showed a relatively low quantity of ISGs expression. The comparison of the overall ISGs expression at first surgery and second surgery highlighted the activation of IFN-responsive genes at second surgery suggesting the occurrence of the local delivery within the TME of biologically active IFN-a. CONCLUSION The results provide initial evidence of Temferon’s potential to modulate the TME of GBM patients.
P19.08.B INCREASED CORTICAL EXCITABILITY TO TRANSCRANIAL MAGNETIC STIMULATION CONTRIBUTE TO EPILEPTOGENESIS IN IDH1-MUTANT GLIOMAS
Authors: G Naros, M Gorbachuk, K Machetanz, M T Leao, S Wang, J Honegger, M Tatagiba
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND In-vitro studies indicate that gliomas with a mutation of the isocitrate dehydrogenase (IDH) increase neuronal excitability of the peritumoral cortex contributing to epileptogenesis in these patients. However, in-vivo evidence is missing. This study evaluates the electric characteristics of the brain-tumor-interface (BTI) relative to the IDH mutation status. MATERIAL AND METHODS To investigate peritumoral cortical excitability (CE), we applied 5258 pulses of transcranial magnetic stimulation (TMS) at the BTI of IDH-mutant (IDH-mt) and IDH-wildtype (IDH-wt) glial tumors in 39 patients. CE was assessed by the resting motor threshold (RMT) and the synchronized electromyographic (EMG) activity (i.e., event-related spectral perturbation, ERSP) after TMS. ERSP values were related to the IDH status, tumor grading, antiepileptic drug intake (AED) and the spatial relationship to the tumor borders. RESULTS There was not significant group difference in RMT. TMS to the BTI triggered an EMG synchronization decreasing linearly with the distance to the functional hotspot. In contrast, IDH-mt gliomas demonstrated an increased cortical output of the peritumoral brain tissue compared to IDH-wt gliomas. This effect was not attributable to AED intake or other histological and molecular characteristics. Notably, cortical hyperexcitability was detectable well beyond the tumor border. CONCLUSION s: This study provides in-vivo evidence of cortical hyperexcitability at the BTI of IDH-mt gliomas which could contribute to the epileptogenesis in these patients.
P11.31.B LEPTOMENINGEAL SPREAD AFTER POSTOPERATIVE STEREOTACTIC RADIOTHERAPY FOR BRAIN METASTASES
Authors: M P Hakstege, M Kiderlen, J Crouzen, R Hagenbeek, R Wiggenraad, R Nandoe Tewari, M Kerkhof, M Vos, N van der Voort van Zyp, M Mast, A Petoukhova, M Broekman, J Zindler
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Stereotactic radiotherapy (SRT) is the preferred treatment after surgical resection of brain metastases to improve local tumour control compared to observation. Some recent studies suggest that leptomeningeal metastases (LMM) occur more often after postoperative SRT compared to primary SRT with brain metastases in situ. This may be caused by tumour cells spillage during surgery. The aim of this study was to determine the incidence of LMM after postoperative SRT of brain metastases in our institution. MATERIAL AND METHODS All patients treated with postoperative SRT for brain metastases in our hospital between 2015 and 2020 were included in this retrospective analysis. LMM was diagnosed by a neuro-radiologist (RH) on a cerebral MRI. LMM, overall survival, and time to local recurrence (LR) were estimated from date of SRT, using the Kaplan-Meier method. RESULTS In total, 53 patients with 84 brain metastases were included in the analysis. Median age at SRT was 58 years (range 45 - 75 years). Median survival in this cohort was 16 months (IQR 9 - 26 months). Eight of 53 patients (15%) developed LMM at a median of 9 months after SRT. Using Kaplan-Meyer analysis, the incidence of LMM at 1 and 2 years was 15% and 19%, respectively. Twelve patients (23%) of 53 experienced LR at a median of 9 months. The 1 and 2-year actuarial incidence was 14% and 35%, respectively. CONCLUSION In our cohort, the incidence of LMM after postoperative SRT for brain metastases is comparable to other studies. Studies are needed to determine whether the incidence of LMM after postoperative SRT can be reduced.
P07.08.A DEVISING AN EXOSOMES CONTROLLED-RELEASE HYDROGEL FOR GLIOBLASTOMA THERAPY
Authors: Z HE, Z Meng, G Wang
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND An efficient therapeutic method for glioblastoma hasn’t been founded. Nowadays, the combination of tumor surgery resection and chemoradiotherapy show limited outcomes even implanting a drug-loaded wafer on the tumor resection cavity during the surgery. Although Local drug delivery improves the adverse effects of intravenous chemotherapy drug injection, the low efficiency of drug transmembrane transportation still leads to poor therapeutic outcomes. Meanwhile, the stiff wafer is not able to perfectly match the irregular shape of the resection cavity. Recently, drug-loaded nanoparticles coated by tumor-derived exosomes applied in tumor-targeting drug delivery were frequently reported. The unique feature of tumor-homing, immune evasion of tumor-derived exosomes was used to improve the delivery efficiency, however, the therapeutic efficiency is weakened by liver filtration and the blood-brain barrier. MATERIAL AND METHODS For enhancing the therapeutic efficacy and compatibility of tumor resection cavity, in this project, a novel injectable hydrogel carrying DOX-loaded nanoparticles coated by tumor-derived exosomes, called Exo-DMSNs@CS, for intra-operative therapy of glioblastoma was devised. The doxorubicin-loaded nanoparticles encapsulated by tumor-derived exosomes (Exo-DMSNs) were integrated into body-temperature sensitive chitosan hydrogel, then injected into the tumor resection cavity and gelation along the shape. By passing the blood-brain barrier, the therapeutic efficacy can be improved by elevating the delivery efficiency induced by the released tumor-targeting Exo-DMSNs. RESULTS The hydrogel Exo-DMSNs@CS was successfully fabricated and contained features of thermosensitive, in vivo controlled releasing, in vitro tumor-targeting, and biocompatible. For simulating the scenario of intra-operative therapy, the Exo-DMSNs@CS was evaluated in the mice orthotopic GBM resection model. The decreased relapse speed and extended survival showed in the Exo-DMSNs@CS compared to DMSNs@CS demonstrated that the tumor-exosomes improve the prognosis of the mice. Moreover, the acceptable side effect was also confirmed. CONCLUSION The Eco-DMSNs@CS is suitable for therapy with better efficiency compared to traditional local drug delivery. This research provides a new strategy for glioblastoma patients and data support for similar product devising.
P21.04.A IMPROVEMENTS IN SURVIVAL FOR GLIOBLASTOMA IN THE POST-STUPP PROTOCOL ERA
Authors: C Neff, M Price, G Chavez, C Proescholdt, C Kruchko, G Cioffi, K Waite, J Barnholtz-Sloan, Q T Ostrom
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The Stupp protocol was accepted as standard of care for glioblastoma in 2005, and has led to significant increases in overall survival. Prior analyses have identified additional survival gains post-Stupp, though the source of these is unknown. In this analysis, we leveraged two large datasets to identify trends in survival and potential treatment factors associated with these improvements. MATERIAL AND METHODS Provider-side commercial claims data were obtained from IQVIA for adults (18+ years) diagnosed with malignant brain tumor (ICD-9/ICD-10:191.0-191.9/C71.0-C71.9) from 2015-2021 who received biopsy/resection and temozolomide within 60 days of diagnosis. Treatment patterns were determined using ICD-9/ICD-10 procedure and HCPCS/CPT codes. Death was determined by CPT codes or last claim followed by ≥30 days of no claims. Elixhauser comorbidity score was generated prior to diagnosis. Population-based survival data were obtained from the National Program of Cancer Registries (NPCR) from 2004-2018 for microscopically-confirmed adult (18+ years) glioblastoma cases receiving surgery and radiation. Median survival was estimated using Kaplan-Meier regression, and cox proportional hazards models were used to assess potential prognostic factors. Survival analyses were censored at 36 months. RESULTS The IQVIA dataset had 18,883 individuals and NPCR had 92,540 individuals identified as being diagnosed with glioblastoma and meeting treatment criteria. Median survival among IQVIA cases was 13.9 months (95%CI=13.7-14.1), and 14 months (95%CI=14-14) in NPCR. Median survival in NPCR increased from 11 months in 2004-2006, to 14 months in 2016-2018. Within IQVIA, 19% of individuals had ≥1 claim for Bevacizumab and 15.5% had ≥1 claim for tumor treating fields (TTFields). Use of TTFields and/or Bevacizumab in treatment were associated with significantly improved survival after adjustment for age, sex, and comorbidities. CONCLUSION s: Survival in glioblastoma continues to improve over time, which may be due to developments in therapeutic approaches. Assessment of population-level survival patterns is essential for understanding the impact of treatment advancements.